Protein quality control in the nervous system is increasingly recognized to be a major factor in normal brain function and in neurodegenerative diseases. The overall objective of this proposal is to develop an understanding of how neurons maintain protein homeostasis and regulate the destruction of misfolded or unassembled glycoproteins. Specifically, my proposed research will focus on a novel brain-enriched E3 ubiquitin ligase, Fbx2p, which has been proposed to regulate the destruction of N-linked, high-mannose glycoproteins. In the first Aim, co-expression studies in cell models will be used to define the role of Fbx2p in the regulation of ion channel glycoproteins, with the N-methyI-D-aspartate receptor (NMDAR) serving as a model case. Further studies in Aim 1 will define changes in the sub-cellular localization of Fbx2p that may occur in response to ER stress, which may provide insight into this protein's mechanism(s) of action. In the second Aim, an Fbx2 knockout mouse recently created in our laboratory will be examined with a battery of behavioral, immunohistochemical and proteomics approaches to define the role of Fbx2p in neurons in vivo. The proposed experiments are significant because they should provide insight into how neurons regulate normal and abnormal glycoproteins, including ion channels, and increase fundamental knowledge about the newly discovered Fbx2p class of ubiquitin ligases.